AN ASYMPTOMATIC GERMLINE MISSENSE BASE SUBSTITUTION IN THE HYPOXANTHINE PHOSPHORIBOSYLTRANSFERASE (HPRT) GENE THAT REDUCES THE AMOUNT OF ENZYME IN HUMANS

A 40-year-old normouricemic (5.5 mg/dl) male showed 46% hemolysate and 37% lymphoblast hypoxanthine phosphoribosyltransferase (HPRT) activit ies but was otherwise completely free of symptoms. His genomic DNA and cDNA had a missense base substitution (CAT-to-CGT in codon 60) leadin g to the amino-acid substitution His-to-Arg. Western blot analysis rev ealed that the amount of HPRT protein in lymphoblasts from this indivi dual was 25%-50% of normal cells, suggesting that the decrease in the amount of enzyme protein was responsible for the partial deficiency. T his provides the first clear evidence that a genomic missense mutation at the HPRT focus leads to a decrease in the amount of the enzyme pro tein but that otherwise it has no evident adverse effects in the hemiz ygote (asymptomatic mutation).